Nuclear RIPK3 and MLKL contribute to cytosolic necrosome formation and necroptosis

Communications Biology

Ria Roelandt¹  Yann Estornes¹  Inge Bruggeman²  Kathrin Weber²  Peter Vandenabeele² 

[1]Department of Biomedical Molecular Biology, Ghent University, Technologiepark 927, Zwijnaarde-Ghent, Belgium

[2]VIB Inflammation Research Center, Technologiepark 927, Zwijnaarde-Ghent, Belgium

DOI  :  10.1038/s42003-017-0007-1

学科分类：生物科学（综合）

来源: Nature Publishing Group

【 摘 要 】

Necroptotic signaling converges in the assembly of a cytosolic signaling platform, the necrosome, with the activation of its downstream effector, MLKL. RIPK1 and RIPK3, key components of the necrosome, act as signaling intermediates for the activation of MLKL. We report that RIPK3 and MLKL continuously shuttle between the nucleus and the cytoplasm, whereas RIPK1 is constitutively present in both compartments. During TNF-induced necroptosis, nuclear RIPK1 becomes ubiquitinated, after which nuclear MLKL becomes phosphorylated and oligomerized. Pharmacological inhibition of the nuclear export machinery leads to retention of RIPK3 and MLKL in the nucleus, prevents the nucleation of cytosolic RIPK3/MLKL oligomerization, and reduces cell death. Our results suggest that passage of necroptotic signaling components through the nucleus is a mechanism for regulating cytosolic necrosome formation and consequently necroptotic cell death.

【 授权许可】

CC BY